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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3798_Библиотеки_им_академика_М_И_Перельмана.pdf
Chapter 3
Hereditary and Familial Lymphedema
Kimberly A. Jones and Marlys H. Witte
Introduction
Just 10 years ago, a chapter could not have been written about the genetic basis of
familial or hereditary lymphedema. Whereas the familial or hereditary occurrence
of peripheral lymphedema has been described for at least 150 years in the literature,
along with numerous syndromes listed in the database Online Mendelian inheritance in Man (OMIM™),1 it was not until 2000 that the first of a series of unrelated
“lymphedema genes” was discovered. The location had been identified on the long
arm of chromosome 5 two years earlier by three independent research groups, but
was not pinpointed.
to the disease now have been identified using new molecular tools. Together with
advances in understanding the growth and development of the lymphatic vasculature (lymphvasculogenesis and lymphangiogenesis) and diverse lymphatic functions, which have uncovered an array of candidate genes underlying these processes,
the field is advancing at a much faster pace. Some of the genes identified to date
seem to have a clear function related to the lymphatic system such as the mutation
in the FLT4 gene, which encodes the vascular endothelial growth factor receptor-3
gene (VEGFR3), important in lymphatic vessel development and function. Other
genes (e.g., FOXC2) have identified proteins important in lymphatic structures as
well as other organs, thus explaining the unique and at times baffling phenotypes of
and within these syndromes. Some gene discoveries have been the stimulus to look
at new pathways or to fill in steps or interrelationships in established pathways in
lymphatic growth, development, and function. Detailed description and improved
classification and reporting of these syndromes and further imaging studies to more
precisely define lymphatic phenotypes (including carriers who may not exhibit overt
lymphedema, but have structurally/functionally abnormal lymphatic vessels) will
2-4
In a few of the other described syndromes, genes contributing
M.H. Witte (*)
Department of Surgery, University of Arizona College of Medicine,
Tucson, AZ, USA
B.-B. Lee et al. (eds.), Lymphedema,
DOI 10.1007/978-0-85729-567-5_3, © Springer-Verlag London Limited 2011
29
30 K.A. Jones and M.H. Witte
Genetics for lymphologists
Phenotyping Genotyping Translation
Clinical
Evaluation
Pedigree
Consent
DNA
Collection
Analysis Mutation
Counseling
Management
Research
Fig. 3.1 Genetics for lymphologists: the work-up. See text for details (Reproduced with permission, The International Society of Lymphology)
allow use of more precise molecular tools to continue to help identify specific loci
responsible for these often multi-system disorders and to carry out pre-natal or
post-natal screening for detection. Moreover, once the molecular defects are uncovered and understood, more targeted therapeutic agents are likely to be developed.
Molecular Lymphology
The true incidence of primary lymphangiodysplasias or lymphedema (LE-AD) syndromes is hard to quantify (perhaps as many as one third of all lymphedemas, except
in areas endemic for lymphatic filariasis, with hundreds of millions afflicted), and
birth registries have not recorded lymphedema incidence. Only a small percentage
(an estimated 5–10%) of primary lymphedema patients give a family history of the
condition; however, lack of recognition could lead to underreporting. In disorders
for which there are multiple congenital abnormalities shared within a family or
group of individuals, a common defect(s) early in development is/are most likely
compared with disorders for which the abnormalities appear to have a later onset or
pubertal onset. Later onset or pubertal onset syndromes are more suggestive of
incomplete penetrance, genetic polymorphisms, different molecular deficits within
a common pathway, or more complicated variables, such as epigenetics and other
environment-related factors.
During the clinical work-up (Fig. 3.1 and see below), once a common lymphedema manifestation and/or lymphovascular phenotype has been described
within a family or group of families, a method known as reverse genetics can be
applied. DNA from a large family or families can be collected and evaluated for
short tandem repeats within each chromosome in an attempt to pinpoint the location of a gene associated with the affected phenotype. Once that location is identified, it can be searched further for possible candidate genes and analyzed for
mutations. Forward genetics can be utilized when a candidate gene that is important
3 Hereditary and Familial Lymphedema
31
in lymphatic function has been identified. Animal models can be produced with
intentionally absent (knock-out) or overactive (transgenic) gene(s) to see if the
expected or observed phenotype can be recapitulated. The function of any potentially involved genes can then be explored in great detail by developing animal
models and by studying other genes and proteins related to the known target gene.
Environmental influences through the study of proteomics can be performed in
these animal models in addition to other in vivo experiments. Well-designed animal
models can become the initial testing ground for future therapies.
Work-up
Despite major advances in the understanding of lymphangiogenesis with the discovery of the lymphatic-directed VEGFs (C and D) and related interacting proteins,
linkage between the clinical phenotype and genotype is challenging. There are still
many unknown genes or epigenetic influences to be discovered. When individuals
or families with primary lymphedema in addition to other phenotypic abnormalities
are identified, further work-up is a crucial step in understanding these disorders in
the future. Referral to a multi-disciplinary group that specializes in the genetics of
lymphangiogenesis is an important part of that work-up. Detailed history and
phenotypic evaluation of the patient and any or all related family members may be
necessary to note other subtle findings. Tools such as high-resolution dynamic
lymphangioscintigraphy,5 fluorescent microlymphangiography,6 and magnetic resonance imaging,7 with and without contrast medium administration, can delineate the
number, size, and pattern of lymphatic growth or malformation and functional
details such as chylous and non-chylous reflux, and these features can be followed
over time. Defining the phenotype of the underlying abnormality (primary aplasia,
hypoplasia, hyperplasia, or acquired dysplasia) is pertinent for classification of the
functional defect and to compare similarities and differences among affected patients
and families. High-resolution chromosomal analysis, linkage analysis, fluorescence
in situ hybridization, and polymerase chain reaction are all molecular methods that
may help identify candidate loci or associated genetic mutations or aberrancies,
using both forward and reverse genetics. The type of syndrome (hereditary or sporadic) determines the best method of testing. Mutations can also be somatic (acquired
genetic change after conception) and therefore may not be passed on to offspring or
affect every organ. For this reason, biopsies of intestinal or pulmonary parenchyma
also may be indicated in syndromes primarily affecting visceral organs only.
Germline mutations, present at conception, are often passed on to offspring
with associated syndromes. Often, mutations, either acquired or inherited, of members in a critical part of a shared pathway, can cause the same clinical consequences.
By comparing individuals or families with those with similar syndromes, it is more
likely for an error to be identified in a shared pathway of development if they do
not share the same mutation. Timely and concise reporting of the findings allow
for important collaborations, which are imperative in the study of rare disorders.
32 K.A. Jones and M.H. Witte
All of these efforts, along with the continued study of secondary (acquired) dysfunction and embryological development of the lymphatic system, should ultimately
lead to better therapeutic options for those suffering from these disorders.
Syndromes
The definition of a syndrome can be described as any combination of signs and
symptoms that are indicative of a particular disease or disorder. Syndromes with an
inherited component are often listed in the frequently updated Online Mendelian
Inheritance in Man (OMIMTM) catalog, which focuses mainly on inherited, or heri-
table, genetic diseases. It lists the associated phenotypes and linked genes when the
molecular basis is unknown.1 When the OMIM™ database I searched, using either
“lymphedema” or “lymphangiectasia,” over 56 entries are found. Some of these are
duplicate entries, variant forms of another syndrome, or do not appear to have primary lymphedema as a major component, leaving a total of 38 syndromes including
the two most commonly described syndromes, Milroy and Meige syndrome. In
addition, Hennekam presented five more syndromes at the National Lymphedema
Network Biennial Conference in Orlando, Florida, September 2000 that were not
listed in OMIM™, but which have been previously published and reviewed
(Fig. 3.2; Table 3.1).
Genes not associated with a particular syndrome have been identified in families
with inherited forms of lymphedema and include HGF, MET,12 and, most recently,
GJC2.13 HGF encodes for hepatocyte growth factor and binds with high affinity to
its receptor MET. Both genes (HGF/MET) were thought to be candidate genes for
lymphedema after an observation that they were both expressed in lymphatic
endothelial cells, but not blood vascular endothelial cells. Mutational analysis identified six specific mutations in HGF and MET that were considered to be causal as
they were found only in hereditary lymphedema probands and their families, were
not present in controls, and caused a mutation in a functional region of the gene
thought to disrupt HGF/MET signaling. The phenotypic description of these families or individuals associated with a loss of HGF/MET was not given.12 Additionally,
GJC2, the gene for connexin 47 (Cx47), located on chromosome 1q41-q42, was
found to be expressed only in lymphatic endothelial cells (LECs) and not blood
endothelial cells (BECs), and was also investigated in families with hereditary lymphedema. Six different mutations were identified, but a clearly distinct phenotype
was not identified.
13
Clinical syndromes with altered lymphovascular phenotypes or lymphedemaangiodysplasia (LE-AD) are often described by their inheritance patterns, age at
onset, and body sites affected. Within both the families and syndromes, there is
clinical variability suggestive of reduced penetrance, genetic heterogeneity, epigenetic and environmental influences, as well as other unrecognized molecular
phenomena. Most LE-AD syndromes have congenital onset of lymphedema of the
lower limbs. However, others have more extensive edema, chylous ascites, pleural
effusions, visceral lymphangiectasias, or other lymphatic growth disturbances such
as cystic hygromas, lymphangiomas, fetal hydrops or fetal demise.
8,9
3 Hereditary and Familial Lymphedema
[left], Irrthum
2
33
Fig. 3.2 Milroy lymphedema (left), lymphedema distichiasis syndrome showing leg lymphedema, tetralogy of Fallot in a young boy, and a double row of
[right])
11
[middle right], and Alders et al.
10
et al.
eyelashes (middle left), hypotrichosis–lymphedema–telangectasia (middle right), and generalized lymphatic dysplasia syndrome (Hennekam) (right) syn-
dromes demonstrating a wide variation in familial lymphedema phenotypes (Reproduced and composited with permission from Evans et al.
34 K.A. Jones and M.H. Witte
Table 3.1 List of lymphedema-associated syndromes and genes identified in hereditary
lymphedema
OMIM listed and reference number
LE–distichiasis 153400
Cholestasis–LE (Aagenaes) (CLS) 214900
LE-Hypoparathryoidism 247410
LE, microcephaly, chorioretinopathy 152950
LE, congenital recessive (Mucke) 247440
LE–ptosis 153000
Hennekam lymphangiectasia 235510
LE, cerebral arteriovenous anomaly 152900
Yellow nail syndrome 153300
LE, ASD, and facial changes 601927
OL-EDA-ID 300301
Noonan syndrome 163950
German syndrome 231080
Campomeilia, cumming type 211890
Fabry disease, variant 301500
Aarskog syndrome, variant 100050
Lissencephaly–cerebellar hypoplasia–LE 257320
Gonadal dysgenesis (GD, XY) 306100
Hydrops fetalis, idiopathic (Njolstadt) 236750
Chylous ascites, autosomal recessive 208300
Prolidase deficiency 170100
Intestinal lymphangiectasia 152800
NAGA deficiency (NAGA) 104170
Aplasia cutis congenita with IL 207731
Mullerian Derivatives – LA–polydactyly (Urioste syndrome) 235255
Pulmonary cystic lymphangiectasia 265300
CDG subtype (Jaeken) 602579
Nevo syndrome 601451
PEHO syndrome 260565
Hypotrichosis–LE–telangiectasia 607823
Tuberous sclerosis, variant 191100
Non-OMIM listed
Posterior choanal atresia–LE (Sheikh)
LE–leukaemia–deafness (Emberger) syndrome LE–cleft palate (Figueroa)
syndrome
Microcephaly – cutis verticisggyrata–LE
Mandibulofacial dysostosis–LE syndrome
Genes associated with hereditary cases of lymphedema and reference number
CCBE1- collagen and calcium binding
EGF-domain containing protein 235510
SOX18- SRY-Box 18 607823
HGF – Hepatocyte growth factor 142409
MET – Met protooncogene 164860
GJC2 – Gap junction protein-gamma2 608803
Chromosomal aberrancies and syndromes associated with lymphedema
and reference number
Turner syndrome (XO) *many
Noonan syndrome 163950
Down syndrome (trisomy 21) 190685
3 Hereditary and Familial Lymphedema
35
Mutations in four different genes have been implicated in the origin of four distinct familial lymphedema–angiodysplasia (LE-AD) syndromes (Fig. 3.2). Within
these syndromes not all members have the specific mutation, yet appear to share the
same phenotype and typical inheritance. Some members of families with autosomal
dominant Milroy disease show different mutations within the gene FLT/VEGFR3
on chromosome 5q35.3.
14,15
VEGFR3 is a tyrosine growth factor receptor for members of the vascular endothelial growth factor family (VEGFC, VEGFD), and these
pathways are important in lymphatic vessel growth and remodeling.16 In autosomal
dominant lymphedema–distichiasis (double row of eyelashes) with onset of peripheral lymphedema at puberty, mutations in FOXC2, a forkhead transcription factor,
on chromosome 16q24.3, have now been consistently documented in more than 30
individuals.
17,18
More recently, one individual with the classic phenotype associated
with lymphedema–distichiasis syndrome was found to have a duplicated 5¢ region
of the FOXC2 gene, suggesting another mechanism in this pleiotrophic pathway
leading to the characteristic phenotype.19 Hennekam syndrome, an autosomal recessive disorder, characterized by lymphedema, lymphangiectasias, mental retardation,
and unusual facies has been well described for years. Linkage analysis on three
families with this syndrome has led to the identification of a chromosomal region
18q21.32 that contains the gene for CCBE1, the human ortholog of a gene essential
for lymphangiogenesis in zebrafish.
11,20
Mutations in SOX18, a transcription factor
located on chromosome 20q13, have been reported in association with both an
autosomal recessive and autosomal dominant (or gonadal mosiacism) form of
hypotrichosis–lymphedema–telangiectasia.
10
The two most common and first described syndromes are Milroy and Meige syndrome. Milroy’s (or Type I) is generally inherited in an autosomal dominant fashion
and leads to a disabling and disfiguring swelling of the extremities. The usual onset
is at birth, and the lymphedema is usually more severe in the lower extremities. There
can be variation in this pattern both within and between families that have the same
mutation, and some families/individuals have similar phenotypes with lack of mutation. The penetrance is reported to be 80%, and clearly there are many as yet unexplained environmental or biological factors involved.21 Linkage analysis on large
families identified the loci for the gene FLT4 on chromosome 5q35.3, which encodes
the VEGFR3 receptor, and since then several mutations in this gene have been
described, all occurring in the tyrosine kinase domain of the VEFR3 receptor.
2,4,21-23
In a search for other possible candidates responsible for this phenotype, ligands for
VEFGR3 were evaluated. Mutational screening of the gene that encodes VEGFC, a
lymphatic directed endothelial growth factor, failed to identify any mutations in individuals with Milroy disease lacking a mutation in FLT4. Unlike other members of
the vascular endothelial factor family (VEGFA, VEGFC, VEFGD), Vegfc is crucial
for the proper development of the lymphatic system, as demonstrated in mice.
24
Meige syndrome (or Type II), also inherited in an autosomal dominant-type fashion, presents later in life, usually at the time of puberty, tends to affect patients
below the waist, and is not associated with a specific mutation.
25
Other syndromes
also have pubertal type onset, but appear to have other specific associated abnormalities. For example, the lymphedema–distichiasis (LD) syndrome mentioned
36 K.A. Jones and M.H. Witte
above presents with later onset lymphedema and has the unique feature of distichiasis, which is a double row of eyelashes. Most patients with this syndrome have a
mutation in the gene for the transcription factor FOXC2, which is not seen in patients
with what appears classically to be Meige syndrome. Another syndrome, Yellow
Nail (YNS), can resemble Meige syndrome, with later onset lymphedema affecting
similar areas. However, patients with YNS have affected nails and often have respiratory involvement with chylothorax. YNS is now thought to be a more sporadic
rather than a dominantly inherited condition.
26
The remaining syndromes with primary lymphedema reported in OMIM™ and
by Hennekam are less common and are frequently associated with other specific
phenotypic abnormalities often in multiple organ systems (Table 3.1). An extensive literature review of the original publications focusing on inheritance, clinical
information, and other reported phenotypic abnormalities in 36 of these syndromes was published by Northup et al. in the journal Lymphology in 2003. This
review identified nine syndromes with autosomal dominant inheritance, 21 syndromes with autosomal recessive inheritance, and six syndromes with X-linked
inheritance. The most commonly affected systems outside of the lymphatic system included the ocular system, dysmorphic facies, genitourinary and gastrointestinal systems, skeletal and growth abnormalities, vascular and hematological
disorders, immunological disorders, central nervous system, and dermatological
manifestations.9 Identifying other abnormalities in other organ systems that appear
to segregate with primary lymphedema can help pinpoint possible defects in similar developmental pathways or pathways affected by similar environmental or epigenetic influences. The careful observation and reporting of associated dysmorphic
features can help better define phenotypes within the LE-AD syndromes.
Abnormalities in several organ systems are commonly reported, and with refined
research into these associated abnormalities, we can identify similar developmental pathways, events during embryogenesis, or perhaps environmental influences
explaining reduced penetrance or later onset. Examples of the types of systems
involved and frequencies are displayed in Fig. 3.3.
Chromosomal Aneuploidies and Sporadic Syndromes
Lymphedema-angiodyplasia syndromes span a wide spectrum of not only familial
disorders, but also those associated with chromosomal abnormalities or mutations
that are of sporadic origin (Table 3.1). Chromosomal aneuploidy (trisomy 13, 18,
21, and 22), Klinefelter XXY, and Turner syndrome (XO), all caused by abnormal
chromosomal division at conception, can be associated with an impaired lymphatic
system and clinical lymphedema. However, not all individuals are affected, and
some of these syndromes, such as Turner’s, can improve with time, suggesting that
lymphatic development in utero might be under different influences than other lymphedema syndromes, which either stabilize or worsen over time. Other isolated
reports have implicated other chromosomes.
3 Hereditary and Familial Lymphedema
30
25
20
15
10
5
0
Facial Ocular Integument/
Nails
Organ system involvement
# Syndromes
GI GU Growth Pulmonar y Cardiac Cranial CNSMR Cancer
12 34 56789
10 11 12 13 14 15 16 17 18
19
Genes
Aneuploidy
Rearrangements
Lymphatic growth factors/receptors
20 21 22 YX
37
Fig. 3.3 Phenotypic abnormalities (organ system involvement) commonly associated with the 40
OMIM-listed hereditary LE-AD syndromes. GI gastrointestinal, GU genitalurinary, MR mental
retardation (Reproduced with permission from Northup et al.
9
)
Fig. 3.4 Genomics–proteomics of lymphedema–angiodysplasia syndromes displayed on schematized human chromosomes (Modified with permission, Witte et al.
Figure. 3.4 summarizes the location of documented or suspected candidate genes/
chromosomal abnormalities underlying LE-AD syndromes.
28
)
38 K.A. Jones and M.H. Witte
Conclusion
Despite major advances in the understanding of lymphangiogenesis since the first
review article in 1997,27 just prior to the discovery of VEGF-C, there are clearly still
many unknown genes or epigenetic influences to be discovered. The high degree of
variability and other compounding influences (both genetic with related pathways
and environmental) make the ability to define a phenotype from any given genotype
nearly impossible at this time. However, advances have been made when individuals or families with primary lymphedema are identified with an appropriate clinical
work-up. Referral to a multi-disciplinary group that specializes in the genetics of
lymphangiogenesis is an important part of that work-up. Detailed history taking and
phenotypic evaluation of the patient and any or all related family members may be
necessary to note other subtle findings. Tools such as high-resolution imaging and
sophisticated molecular testing, as described above, will continue to provide critical
data on the specific structural problem, pattern, and lymphatic dysfunction.
Collaborations and timely and concise reporting of the findings from all areas of
research are also imperative for advancement. With the rapid development of biological therapeutics, certainly restoration of altered pathways will become a viable
possibility, although the obstacles to genetic information and molecular models in
clinical applications will remain a formidable challenge.
Acknowledgments Arizona Disease Control Research Commission Contract #9002, I-103, NIH
HL 71206, and the International Society of Lymphology.
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